EP4023232A1 - Composition pharmaceutique pour le traitement du cancer comprenant un virus anticancéreux, un inhibiteur de point de contrôle immunitaire et une hydroxyurée en tant que principes actifs - Google Patents

Composition pharmaceutique pour le traitement du cancer comprenant un virus anticancéreux, un inhibiteur de point de contrôle immunitaire et une hydroxyurée en tant que principes actifs Download PDF

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EP4023232A1
EP4023232A1 EP19943591.8A EP19943591A EP4023232A1 EP 4023232 A1 EP4023232 A1 EP 4023232A1 EP 19943591 A EP19943591 A EP 19943591A EP 4023232 A1 EP4023232 A1 EP 4023232A1
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Prior art keywords
virus
cancer
hydroxyurea
administered
oncolytic virus
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German (de)
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EP4023232A4 (fr
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Tae-Ho Hwang
Mong Cho
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Bionoxx Inc
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Bionoxx Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/76—Viruses; Subviral particles; Bacteriophages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/76—Viruses; Subviral particles; Bacteriophages
    • A61K35/768—Oncolytic viruses not provided for in groups A61K35/761 - A61K35/766
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
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    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
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    • C07K16/2827—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against B7 molecules, e.g. CD80, CD86
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    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
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    • C12N2710/00011—Details
    • C12N2710/24011—Poxviridae
    • C12N2710/24111—Orthopoxvirus, e.g. vaccinia virus, variola
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    • C12N2710/00011—Details
    • C12N2710/24011—Poxviridae
    • C12N2710/24111—Orthopoxvirus, e.g. vaccinia virus, variola
    • C12N2710/24132—Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent
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    • C12N2710/00011—Details
    • C12N2710/24011—Poxviridae
    • C12N2710/24111—Orthopoxvirus, e.g. vaccinia virus, variola
    • C12N2710/24141—Use of virus, viral particle or viral elements as a vector
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    • C12N2710/00011—Details
    • C12N2710/24011—Poxviridae
    • C12N2710/24111—Orthopoxvirus, e.g. vaccinia virus, variola
    • C12N2710/24161—Methods of inactivation or attenuation
    • C12N2710/24162—Methods of inactivation or attenuation by genetic engineering
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to a pharmaceutical composition for treating cancer, comprising, as active ingredients, an oncolytic virus, an immune checkpoint inhibitor, and hydroxyurea.
  • Oncolytic viruses have excellent tumor-specific targeting ability, proliferation ability in cancer cells, and cancer cell-killing ability. Recently, various clinical studies based on oncolytic viruses have been conducted. In the year 2015, an era of oncolytic virus field began in the US and Europe, as talimogene laherparepvec (T-Vec), which is an oncolytic virus based on herpes simplex virus, was successfully commercialized as a therapeutic agent for advanced melanoma.
  • T-Vec talimogene laherparepvec
  • oncolytic viruses exceeds their own efficacy and the viruses activate tumor immunity, thereby showing their potential as a therapeutic agent that is used in combination with another immunotherapeutic agent.
  • a direct killing effect of the viruses which is caused by cancer cell-specific proliferation thereof, was relatively more important.
  • subsequent clinical studies have found that the key mechanism of oncolytic viruses was the activation of tumor immunity rather than the direct cancer cell-killing effect.
  • therapies in which an oncolytic virus is administered in combination with an immunotherapeutic agent such as an immune checkpoint inhibitor, have recently been developed. It is known that such therapies are possible because the oncolytic virus converts the tumor microenvironment, in which immunity is suppressed, into a tumor microenvironment suitable for immunotherapy.
  • oncolytic virus therapy may result in acute tumor necrosis, durable response, or complete response, but in some cases, may lead to a difficult-to-predict result (pharmacodynamics variability) such as progressive disease or early death.
  • a difficult-to-predict result such as progressive disease or early death.
  • Pexa-vec that is based on a vaccinia virus
  • the present inventors have found that excellent anticancer effect and safety are obtained in a case where an oncolytic virus, an immune checkpoint inhibitor, and hydroxyurea are co-administered to an individual with cancer, as compared with a conventional case where an oncolytic virus is administered alone, or an oncolytic virus and an immune checkpoint inhibitor are co-administered, thereby completing the present invention.
  • a pharmaceutical composition for treating cancer comprising, as active ingredients, an oncolytic virus, an immune checkpoint inhibitor, and hydroxyurea.
  • kits for treating cancer comprising a first composition that includes an oncolytic virus as an active ingredient, a second composition that includes hydroxyurea as an active ingredient, and a third composition that includes an immune checkpoint inhibitor as an active ingredient.
  • a method for treating cancer comprising administering, to an individual with cancer, an oncolytic virus, an immune checkpoint inhibitor, and hydroxyurea.
  • composition which includes an oncolytic virus, an immune checkpoint inhibitor, and hydroxyurea, for the prevention or treatment of cancer.
  • composition which includes an oncolytic virus, an immune checkpoint inhibitor, and hydroxyurea, for the manufacture of a medicament for preventing or treating cancer.
  • the pharmaceutical composition for treating cancer which comprises, as active ingredients, an oncolytic virus, an immune checkpoint inhibitor, and hydroxyurea, of the present invention has excellent anticancer effect and safety as compared with a conventional case where an oncolytic virus is administered alone or an oncolytic virus and an immune checkpoint inhibitor are co-administered. Accordingly, the pharmaceutical composition, which comprises, as active ingredients, an oncolytic virus, an immune checkpoint inhibitor, and hydroxyurea, of the present invention may be effectively used for the treatment of cancer.
  • a pharmaceutical composition for treating cancer comprising, as active ingredients, an oncolytic virus, an immune checkpoint inhibitor (ICI), and hydroxyurea.
  • an oncolytic virus comprising, as active ingredients, an oncolytic virus, an immune checkpoint inhibitor (ICI), and hydroxyurea.
  • ICI immune checkpoint inhibitor
  • the oncolytic virus, the immune checkpoint inhibitor, and the hydroxyurea, which are included in the pharmaceutical composition may be co-administered simultaneously, sequentially, or in reverse order.
  • the oncolytic virus, the immune checkpoint inhibitor, and the hydroxyurea may be administered simultaneously.
  • the hydroxyurea may be administered first, followed by the immune checkpoint inhibitor, and then the oncolytic virus.
  • the hydroxyurea may be administered first, followed by the oncolytic virus, and then the immune checkpoint inhibitor.
  • the hydroxyurea may be administered first, followed by simultaneous administration of the oncolytic virus and the immune checkpoint inhibitor.
  • the oncolytic virus may be administered first, followed by the hydroxyurea, and then the immune checkpoint inhibitor.
  • the oncolytic virus may be administered first, followed by the immune checkpoint inhibitor, and then the hydroxyurea.
  • the oncolytic virus may be administered first, followed by simultaneous administration of the hydroxyurea and the immune checkpoint inhibitor.
  • the immune checkpoint inhibitor may be administered first, followed by the hydroxyurea, and then the oncolytic virus.
  • the immune checkpoint inhibitor may be administered first, followed by the oncolytic virus, and then the hydroxyurea.
  • the immune checkpoint inhibitor may be administered first, followed by simultaneous administration of the oncolytic virus and the hydroxyurea.
  • the hydroxyurea may be administered first, followed by the oncolytic virus, followed by the immune checkpoint inhibitor, and then the hydroxyurea again.
  • the hydroxyurea may be administered first, followed by the immune checkpoint inhibitor, followed by the oncolytic virus, and then the hydroxyurea again.
  • the hydroxyurea may be administered first, followed by simultaneous administration of the oncolytic virus and the immune checkpoint inhibitor, and then the hydroxyurea again.
  • the hydroxyurea may be administered first, followed by the oncolytic virus, followed by the hydroxyurea again, and then the immune checkpoint inhibitor.
  • the hydroxyurea may be administered first, followed by the immune checkpoint inhibitor, followed by the hydroxyurea again, and then the oncolytic virus.
  • the hydroxyurea may be administered first, followed by the oncolytic virus, followed by the hydroxyurea again, followed by the immune checkpoint inhibitor, and then the hydroxyurea again.
  • the hydroxyurea may be administered first, followed by the immune checkpoint inhibitor, followed by the hydroxyurea again, followed by the oncolytic virus, and then the hydroxyurea again.
  • the oncolytic virus may be administered first, followed by the hydroxyurea, followed by the immune checkpoint inhibitor, and then the hydroxyurea again.
  • the immune checkpoint inhibitor may be administered first, followed by the hydroxyurea, followed by the oncolytic virus, and then the hydroxyurea again.
  • the oncolytic virus may be derived from adenovirus, herpes simplex virus, measles virus, lentivirus, retrovirus, cytomegalovirus, baculovirus, adeno-associated virus, myxoma virus, vesicular stomatitis virus, poliovirus, Newcastle disease virus, parvovirus, coxsackievirus, senecavirus, vaccinia virus, or orthopoxvirus.
  • the oncolytic virus may be derived from vaccinia virus, herpes simplex virus, or adenovirus.
  • the vaccinia virus may be, but is not limited to, one of the following vaccinia virus strains: Western Reserve (WR), New York vaccinia virus (NYVAC), Wyeth (The New York City Board of Health; NYCBOH), LC16m8, Lister, Copenhagen, Tian Tan, USSR, TashKent, Evans, International Health Division-J (IHD-J), and International Health Division-White (IHD-W).
  • Western Reserve strain vaccinia virus and the Wyeth strain vaccinia virus were used.
  • the oncolytic virus may be a wild-type virus or a recombinant virus.
  • the recombinant virus may be obtained by deleting at least one gene of the wild-type virus or inserting at least one foreign gene thereinto.
  • the at least one gene of the wild-type virus may be a gene related to viral virulence which encodes any one selected from the group consisting of thymidine kinase (TK), vaccinia growth factor (VGF), WR53.5, F13.5L, F14.5, A56R, B18R, and combinations thereof.
  • the at least one foreign gene may be an immune-promoting gene that encodes any one selected from the group consisting of herpes simplex virus thymidine kinase (HSV-TK), HSV-TK variant, granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), cytosine deaminase (CD), carboxylesterase 1, carboxylesterase 2, interferon beta (INF- ⁇ ), somatostatin receptor 2, and combinations thereof.
  • HSV-TK herpes simplex virus thymidine kinase
  • HSV-TK variant HSV-TK variant
  • GM-CSF granulocyte-macrophage colony-stimulating factor
  • G-CSF granulocyte colony-stimulating factor
  • CD cytosine deaminase
  • carboxylesterase 1 carboxylesterase 2, interferon beta (INF- ⁇ )
  • the recombinant virus may be obtained by deleting TK gene in adenovirus, herpes simplex virus, measles virus, lentivirus, retrovirus, cytomegalovirus, baculovirus, adeno-associated virus, myxoma virus, vesicular stomatitis virus, poliovirus, Newcastle disease virus, parvovirus, coxsackievirus, senecavirus, vaccinia virus, or orthopoxvirus.
  • a recombinant virus obtained by deleting TK gene in a Western Reserve strain vaccinia virus was used, and this recombinant virus was designated as "WR VV tk- ".
  • a recombinant virus obtained by deleting TK gene in a Wyeth strain vaccinia virus was used, and this recombinant virus was designated as "Wyeth VV tk- ".
  • the recombinant virus may be obtained by deleting TK gene and VGF gene in adenovirus, herpes simplex virus, measles virus, lentivirus, retrovirus, cytomegalovirus, baculovirus, adeno-associated virus, myxoma virus, vesicular stomatitis virus, poliovirus, Newcastle disease virus, parvovirus, coxsackievirus, senecavirus, vaccinia virus, or orthopoxvirus.
  • adenovirus herpes simplex virus, measles virus, lentivirus, retrovirus, cytomegalovirus, baculovirus, adeno-associated virus, myxoma virus, vesicular stomatitis virus, poliovirus, Newcastle disease virus, parvovirus, coxsackievirus, senecavirus, vaccinia virus, or orthopoxvirus.
  • the recombinant virus may be obtained by deleting TK gene in and inserting HSV-TK gene into adenovirus, herpes simplex virus, measles virus, lentivirus, retrovirus, cytomegalovirus, baculovirus, adeno-associated virus, myxoma virus, vesicular stomatitis virus, poliovirus, Newcastle disease virus, parvovirus, coxsackievirus, senecavirus, vaccinia virus, or orthopoxvirus.
  • adenovirus herpes simplex virus, measles virus, lentivirus, retrovirus, cytomegalovirus, baculovirus, adeno-associated virus, myxoma virus, vesicular stomatitis virus, poliovirus, Newcastle disease virus, parvovirus, coxsackievirus, senecavirus, vaccinia virus, or orthopoxvirus.
  • the recombinant virus may be obtained by deleting TK gene in and inserting an HSV-TK variant gene into adenovirus, herpes simplex virus, measles virus, lentivirus, retrovirus, cytomegalovirus, baculovirus, adeno-associated virus, myxoma virus, vesicular stomatitis virus, poliovirus, Newcastle disease virus, parvovirus, coxsackievirus, senecavirus, vaccinia virus, or orthopoxvirus.
  • adenovirus herpes simplex virus, measles virus, lentivirus, retrovirus, cytomegalovirus, baculovirus, adeno-associated virus, myxoma virus, vesicular stomatitis virus, poliovirus, Newcastle disease virus, parvovirus, coxsackievirus, senecavirus, vaccinia virus, or orthopoxvirus.
  • a recombinant virus was used, which is obtained by deleting TK gene in a Western Reserve strain vaccinia virus and inserting, into the deleted position, a gene that is represented by SEQ ID NO: 1 and encodes an HSV-TK variant, and this recombinant virus was designated as "WOTS-418".
  • the recombinant virus may be obtained by deleting TK gene in and inserting GM-CSF gene into adenovirus, herpes simplex virus, measles virus, lentivirus, retrovirus, cytomegalovirus, baculovirus, adeno-associated virus, myxoma virus, vesicular stomatitis virus, poliovirus, Newcastle disease virus, parvovirus, coxsackievirus, senecavirus, vaccinia virus, or orthopoxvirus.
  • adenovirus herpes simplex virus, measles virus, lentivirus, retrovirus, cytomegalovirus, baculovirus, adeno-associated virus, myxoma virus, vesicular stomatitis virus, poliovirus, Newcastle disease virus, parvovirus, coxsackievirus, senecavirus, vaccinia virus, or orthopoxvirus.
  • the recombinant virus may be obtained by deleting TK gene in and inserting G-CSF gene into adenovirus, herpes simplex virus, measles virus, lentivirus, retrovirus, cytomegalovirus, baculovirus, adeno-associated virus, myxoma virus, vesicular stomatitis virus, poliovirus, Newcastle disease virus, parvovirus, coxsackievirus, senecavirus, vaccinia virus, or orthopoxvirus.
  • adenovirus herpes simplex virus, measles virus, lentivirus, retrovirus, cytomegalovirus, baculovirus, adeno-associated virus, myxoma virus, vesicular stomatitis virus, poliovirus, Newcastle disease virus, parvovirus, coxsackievirus, senecavirus, vaccinia virus, or orthopoxvirus.
  • the recombinant virus may be obtained by deleting TK gene in and inserting cytosine deaminase (CD) gene into adenovirus, herpes simplex virus, measles virus, lentivirus, retrovirus, cytomegalovirus, baculovirus, adeno-associated virus, myxoma virus, vesicular stomatitis virus, poliovirus, Newcastle disease virus, parvovirus, coxsackievirus, senecavirus, vaccinia virus, or orthopoxvirus.
  • CD cytosine deaminase
  • the recombinant virus may be obtained by deleting TK gene in and inserting somatostatin receptor 2 gene into adenovirus, herpes simplex virus, measles virus, lentivirus, retrovirus, cytomegalovirus, baculovirus, adeno-associated virus, myxoma virus, vesicular stomatitis virus, poliovirus, Newcastle disease virus, parvovirus, coxsackievirus, senecavirus, vaccinia virus, or orthopoxvirus.
  • adenovirus herpes simplex virus, measles virus, lentivirus, retrovirus, cytomegalovirus, baculovirus, adeno-associated virus, myxoma virus, vesicular stomatitis virus, poliovirus, Newcastle disease virus, parvovirus, coxsackievirus, senecavirus, vaccinia virus, or orthopoxvirus.
  • the recombinant virus may be obtained by deleting TK gene in and inserting any two or more genes selected from the group consisting of genes, each of which encodes herpes simplex virus thymidine kinase (HSV-TK), an HSV-TK variant, granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), cytosine deaminase (CD), or somatostatin receptor 2, into adenovirus, herpes simplex virus, measles virus, lentivirus, retrovirus, cytomegalovirus, baculovirus, adeno-associated virus, myxoma virus, vesicular stomatitis virus, poliovirus, Newcastle disease virus, parvovirus, coxsackievirus, senecavirus, vaccinia virus, or orthopoxvirus.
  • HSV-TK herpes simplex virus thym
  • the recombinant virus may be obtained by deleting TK gene and VGF gene in and inserting any one gene selected from the group consisting of genes, each of which encodes HSV-TK, an HSV-TK variant, GM-CSF, G-CSF, CD, or somatostatin receptor 2, and combinations thereof, into adenovirus, herpes simplex virus, measles virus, lentivirus, retrovirus, cytomegalovirus, baculovirus, adeno-associated virus, myxoma virus, vesicular stomatitis virus, poliovirus, Newcastle disease virus, parvovirus, coxsackievirus, senecavirus, vaccinia virus, or orthopoxvirus.
  • genes each of which encodes HSV-TK, an HSV-TK variant, GM-CSF, G-CSF, CD, or somatostatin receptor 2, and combinations thereof, into adenovirus, herpes simplex virus, measles virus, lent
  • gene deletion means that a gene is not expressed due to partial or complete deletion of the gene, or insertion of a foreign gene thereinto. In a case where partial deletion occurs in the gene, some amino acids at the N-terminus or C-terminus of a polypeptide expressed by the gene may be deleted.
  • thymidine kinase refers to an enzyme that is called thymidine kinase and involved in nucleotide biosynthesis.
  • the TK is an enzyme used for nucleotide biosynthesis in both cells and viruses.
  • normal cells do not divide anymore, and thus no TK exists therein; and even for rapidly dividing cells such as hair follicle cells, TK is not present in an amount sufficient for viruses to utilize. From these viewpoints, a virus is allowed to proliferate only in the presence of cancer cells, in which TK is present, by deletion of TK gene therein, so that the cancer cells may be selectively killed.
  • VGF vaccinia growth factor
  • a vaccinia virus replicates better in proliferating cells, and thus may be advantageously used for viral replication in vivo.
  • the virus may additionally undergo deletion of VGF gene in addition to deletion of the TK gene.
  • GM-CSF which is called granulocyte-macrophage colony-stimulating factor, refers to a protein secreted by macrophages, T cells, mast cells, natural killer cells, endothelial cells, and fibroblasts. GM-CSF stimulates stem cells to produce granulocytes (neutrophils, basophils, eosinophils) and monocytes. In addition, GM-CSF rapidly increases the number of macrophages, thereby inducing an immune response.
  • the GM-CSF may be of human origin and may be a protein having the sequence of GenBank: AAA52578.1.
  • CD which is called cytosine deaminase, refers to an enzyme that catalyzes hydrolytic deamination of cytosine into uracil and ammonia.
  • G-CSF which is called granulocyte colony-stimulating factor, refers to a cytokine produced by macrophages, fibroblasts, endothelial cells, and the like upon stimulation by inflammation or endotoxin.
  • the G-CSF promotes production of neutrophils.
  • the G-CSF may be of human origin (rhGCSF) and may be a protein having the sequence of GenBank: AAA03056.1.
  • somatostatin receptor 2 refers to a protein encoded by SSTR2 gene in humans.
  • the somatostatin receptor 2 is expressed mainly in tumors, and patients with neuroendocrine tumors, who overexpress somatostatin receptor 2, show improved prognosis.
  • the somatostatin receptor 2 has capacity to stimulate apoptosis in many cells, including cancer cells.
  • hydroxyurea refers to a compound having the following formula.
  • the hydroxyurea is known as an anticancer agent that inhibits DNA synthesis; however, the exact mechanism thereof is not elucidated.
  • the hydroxyurea may be included in the pharmaceutical composition in the form of a commercialized drug that contains hydroxyurea.
  • Examples of the commercialized drug that contains hydroxyurea may include, but are not limited to, Hydroxyurea ® , Hydrea ® , Droxia TM , Mylocel TM , Siklos ® , and Hydrine ® capsule.
  • the hydroxyurea may be taken orally, and parenteral administration thereof is also possible.
  • a dosage of the oncolytic virus varies depending on the individual's condition and body weight, the severity of disease, the type of drug, the route and period of administration, and may be appropriately selected by a person skilled in the art.
  • the dosage may be such that a patient receives a vaccinia virus at 1 ⁇ 10 5 to 1 ⁇ 10 18 of virus particles, infectious virus units (TCID 50 ), or plaque forming units (pfu).
  • the dosage may be such that a patient receives an oncolytic virus at 1 ⁇ 10 5 , 2 ⁇ 10 5 , 5 ⁇ 10 5 , 1 ⁇ 10 6 , 2 ⁇ 10 6 , 5 ⁇ 10 6 , 1 ⁇ 10 7 , 2 ⁇ 10 7 , 5 ⁇ 10 7 , 1 ⁇ 10 8 , 2 ⁇ 10 8 , 5 ⁇ 10 8 , 1 ⁇ 10 9 , 2 ⁇ 10 9 , 5 ⁇ 10 9 , 1 ⁇ 10 10 , 5 ⁇ 10 10 , 1 ⁇ 10 11 , 5 ⁇ 10 11 , 1 ⁇ 10 12 , 1 ⁇ 10 13 , 1 ⁇ 10 14 , 1 ⁇ 10 15 , 1 ⁇ 10 16 , 1 ⁇ 10 17 , or higher of virus particles, infectious virus units, or plaque forming units, and various numerical values and ranges between the above-mentioned numerical values may also be included therein.
  • the oncolytic virus may be administered at a dose of 1 ⁇ 10 5 to 1 ⁇ 10 10 pfu. More preferably, the oncolytic virus may be administered at a dose of equal to or greater than 1 ⁇ 10 5 and lower than 1 ⁇ 10 9 pfu. In an embodiment of the present invention, the oncolytic virus was administered at 1 ⁇ 10 5 or ⁇ 10 7 pfu.
  • the hydroxyurea may be administered at a dose of 1 mg/kg/day to 100 mg/kg/day, or 10 mg/kg/day to 90 mg/kg/day. Specifically, the hydroxyurea may be administered at a dose of 10 mg/kg/day to 90 mg/kg/day, 15 mg/kg/day to 80 mg/kg/day, 20 mg/kg/day to 70 mg/kg /day, 25 mg/kg/day to 65 mg/kg/day, or 30 mg/kg/day to 60 mg/kg/day. In an embodiment of the present invention, the hydroxyurea was administered at 30 mg/kg/day or 60 mg/kg/day. Depending on the dosage, the hydroxyurea may be administered in divided doses several times a day. Specifically, the hydroxyurea may be administered 1 to 4 times a day or 1 to 2 times a day.
  • the immune checkpoint inhibitor refers to a substance that inhibits the mechanism of cancer cells which interferes with activation of T cells, and may be any one selected from the group consisting of anti-PD-Ll antibody, anti-PD-1 antibody, anti-CTLA4 antibody, anti-PD-L2 antibody, LTF2 control antibody, anti-LAG3 antibody, anti-A2aR antibody, anti-TIGIT antibody, anti-TIM-3 antibody, anti-B7-H3 antibody, anti-B7-H4 antibody, anti-VISTA antibody, anti-CD47 antibody, anti-BTLA antibody, anti-KIR antibody, anti-IDO antibody, and combinations thereof.
  • cancer cells use immune checkpoint receptors to evade immune responses, and representative examples of the immune checkpoint receptor include PD-L1, PD-1, CTLA-4, and the like.
  • an immune checkpoint inhibitor which is a molecule that specifically binds to an immune checkpoint receptor, is used for the treatment of cancer.
  • the first immune checkpoint inhibitor was ipilimumab (Yervoy ® ), which is a monoclonal antibody that specifically binds to cytotoxic T-lymphocyte associated antigen-4 (CTLA-4).
  • the next developed immune checkpoint therapeutic agents were monoclonal antibodies against programmed cell death-1 (PD-1) and a ligand thereof, that is, programmed death ligand-1 (PD-L1).
  • PD-1 programmed cell death-1
  • P-L1 programmed death ligand-1
  • anti-PD-1 antibodies such as nivolumab (Opdivo ® ) and pembrolizumab (Keytruda ® )
  • anti-PD-L1 antibodies such as avelumab (Bavencio ® ), atezolizumab (Tecentriq ® ), and durvalumab (Imfinzi ® ) may be mentioned.
  • GITR glucocorticoid-induced TNFR-related protein
  • KIR killer cell immunoglobulin-like receptor
  • LAG-3 lymphocyte-activation gene-3
  • TIM-3 T-cell immunoglobulin and mucin-domain containing-3
  • TNFRSF4 tumor-necrosis factor receptor superfamily member 4
  • the immune checkpoint inhibitor may be administered at a dose of 0.1 mg/kg to 10 mg/kg, or 1 mg/kg to 5 mg/kg.
  • a dose of 0.1 mg/kg to 10 mg/kg, or 1 mg/kg to 5 mg/kg For example, for Opdivo Injection. that contains nivolumab as an active ingredient, 3 mg/kg may be administered via intravenous instillation over 60 minutes at 2-week intervals; and the usage and dose thereof as a combination therapy may be such that 1 mg/kg is administered via intravenous instillation over 30 minutes.
  • 200 mg may be administered via intravenous instillation over 30 minutes at 3-week intervals.
  • administration thereof is preferably performed in compliance with the usage and dose set by each manufacturer.
  • the cancer may be solid cancer or blood cancer.
  • the blood cancer may be any one selected from the group consisting of lymphoma, acute leukemia, and multiple myeloma.
  • the solid cancer may be any one selected from the group consisting of lung cancer, colorectal cancer, prostate cancer, thyroid cancer, breast cancer, brain cancer, head and neck cancer, esophageal cancer, skin cancer, thymic cancer, gastric cancer, colon cancer, liver cancer, ovarian cancer, uterine cancer, bladder cancer, rectal cancer, gallbladder cancer, biliary tract cancer, pancreatic cancer, and combinations thereof.
  • the pharmaceutical composition of the present invention may further comprise a physiologically acceptable carrier.
  • the pharmaceutical composition of the present invention may further comprise suitable excipients and diluents commonly used in the preparation of pharmaceutical compositions.
  • the pharmaceutical composition may be formulated in the form of an injection according to a conventional method.
  • the pharmaceutical composition may be formulated into sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, or the like.
  • aqueous solutions non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, or the like.
  • propylene glycol polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, or the like may be used.
  • Witepsol TM macrogol, Tween TM 61, cacao butter, laurin fat, glycerogelatin, or the like may be used.
  • the pharmaceutical composition may be administered to a subject in a variety of ways and amounts depending on the patient's condition and the presence or absence of side effects; and the optimal administration route, dosage, and frequency of administration therefor may be selected by a person skilled in the art within a suitable range.
  • the pharmaceutical composition may be administered in combination with another drug or physiologically active substance whose therapeutic effect is known for the disease to be treated, or may be formulated in the form of a combination preparation with the other drug.
  • the pharmaceutical composition may be administered parenterally, and such administration may be performed by any suitable method, such as intratumoral, intraperitoneal, subcutaneous, intradermal, intranodal, intravenous, or intraarterial administration. Among these, intratumoral, intraperitoneal, or intravenous administration may be preferred. On the other hand, the dosage of the pharmaceutical composition may be determined depending on the administration schedule, the total dosage, and the patient's health condition.
  • kits for treating cancer comprising a first composition that includes an oncolytic virus as an active ingredient, a second composition that includes hydroxyurea as an active ingredient, and a third composition that includes an immune checkpoint inhibitor as an active ingredient.
  • the oncolytic virus, the immune checkpoint inhibitor, and the hydroxyurea are as described above for the pharmaceutical composition.
  • a dosage of the first composition varies depending on the individual's condition and body weight, the severity of disease, the type of drug, the route and period of administration, and may be appropriately selected by a person skilled in the art.
  • the dosage may be such that a patient receives a vaccinia virus at 1 ⁇ 10 5 to 1 ⁇ 10 18 of virus particles, infectious virus units (TCID 50 ), or plaque forming units (pfu).
  • the dosage may be such that a patient receives an oncolytic virus at 1 ⁇ 10 5 , 2 ⁇ 10 5 , 5 ⁇ 10 5 , 1 ⁇ 10 6 , 2 ⁇ 10 6 , 5 ⁇ 10 6 , 1 ⁇ 10 7 , 2 ⁇ 10 7 , 5 ⁇ 10 7 , 1 ⁇ 10 8 , 2 ⁇ 10 8 , 5 ⁇ 10 8 , 1 ⁇ 10 9 , 2 ⁇ 10 9 , 5 ⁇ 10 9 , 1 ⁇ 10 10 , 5 ⁇ 10 10 , 1 ⁇ 10 11 , 5 ⁇ 10 11 , 1 ⁇ 10 12 , 1 ⁇ 10 13 , 1 ⁇ 10 14 , 1 ⁇ 10 15 , 1 ⁇ 10 16 , 1 ⁇ 10 17 , or higher of virus particles, infectious virus units, or plaque forming units, and various numerical values and ranges between the above-mentioned numerical values may also be included therein.
  • the oncolytic virus may be administered at a dose of 1 ⁇ 10 5 to 1 ⁇ 10 10 pfu. More preferably, the oncolytic virus may be administered at a dose of equal to or greater than 1 ⁇ 10 5 and lower than 1 ⁇ 10 9 pfu. In an embodiment of the present invention, the first composition was administered at 1 ⁇ 10 5 or ⁇ 10 7 pfu.
  • the second composition may be administered at a dose of 1 mg/kg/day to 100 mg/kg/day, or 10 mg/kg/day to 90 mg/kg/day. Specifically, the second composition may be administered at a dose of 10 mg/kg/day to 90 mg/kg/day, 15 mg/kg/day to 80 mg/kg/day, 20 mg/kg/day to 70 mg/kg /day, 25 mg/kg/day to 65 mg/kg/day, or 30 mg/kg/day to 60 mg/kg/day. In an embodiment of the present invention, the second composition was administered at 30 mg/kg/day or 60 mg/kg/day. Depending on the dosage, the second composition may be administered in divided doses several times a day. Specifically, the second composition may be administered 1 to 4 times a day or 1 to 2 times a day.
  • Administration of the third composition may be performed in compliance with the usage and dose of an immune checkpoint inhibitor included in the third composition, which are set by each manufacturer.
  • the dosage of the third composition may be 0.1 mg/kg to 10 mg/kg, or 1 mg/kg to 5 mg/kg.
  • the cancer may be solid cancer or blood cancer.
  • the blood cancer may be any one selected from the group consisting of lymphoma, acute leukemia, and multiple myeloma.
  • the solid cancer may be any one selected from the group consisting of lung cancer, colorectal cancer, prostate cancer, thyroid cancer, breast cancer, brain cancer, head and neck cancer, esophageal cancer, skin cancer, thymic cancer, gastric cancer, colon cancer, liver cancer, ovarian cancer, uterine cancer, bladder cancer, rectal cancer, gallbladder cancer, biliary tract cancer, pancreatic cancer, and combinations thereof.
  • the first composition, the second composition, and the third composition may further comprise a physiologically acceptable carrier.
  • the pharmaceutical composition of the present invention may further comprise suitable excipients and diluents commonly used in the preparation of pharmaceutical compositions.
  • the pharmaceutical composition may be formulated in the form of an injection according to a conventional method.
  • the first composition, the second composition, and the third composition may be formulated into sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, or the like.
  • aqueous solutions for the non-aqueous solution or the suspension, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, or the like may be used.
  • Witepsol TM As the base of the suppository, Witepsol TM , macrogol, Tween TM 61, cacao butter, laurin fat, glycerogelatin, or the like may be used.
  • the first composition, the second composition, and the third composition may be administered to a subject in a variety of ways and amounts depending on the patient's condition and the presence or absence of side effects; and the optimal administration route, dosage, and frequency of administration therefor may be selected by a person skilled in the art within a suitable range.
  • the pharmaceutical composition may be administered in combination with another drug or physiologically active substance whose therapeutic effect is known for the disease to be treated, or may be formulated in the form of a combination preparation with the other drug.
  • the first composition, the second composition, and the third composition may be administered parenterally, and such administration may be performed by any suitable method, such as intratumoral, intraperitoneal, subcutaneous, intradermal, intranodal, intravenous, or intraarterial administration. Among these, intratumoral, intraperitoneal, or intravenous administration may be preferred.
  • dosages of the first composition, the second composition, and the third composition may be determined depending on the administration schedule, the total dosage, and the patient's health condition.
  • the first composition may be administered twice to an individual, and the administration may be performed at intervals of 7 to 30 days. Specifically, the first composition may be administered at intervals of 7 days, 14 days, 21 days, or 30 days.
  • the second composition may be administered before or after administration of the first composition.
  • the second composition may be continuously administered once a day starting from 3 to 5 days before administration of the first composition, and may be continuously administered once a day for 9 to 28 days starting from within 24 hours of or after 24 hours of administration of the first composition.
  • the second composition may be continuously administered once a day starting from 1 to 3 days before administration of the first composition, and may be administered once a day for 13 days, 17 days, 18 days, or 28 days after administration of the first composition.
  • the third composition may be continuously administered at least once a week for 1 to 10 weeks after administration of the first composition. Specifically, the third composition may be administered continuously at least twice a week for 1 to 8 weeks after administration of the first composition.
  • a method for treating cancer comprising administering, to an individual with cancer, an oncolytic virus, an immune checkpoint inhibitor, and hydroxyurea.
  • the oncolytic virus, the immune checkpoint inhibitor, and the hydroxyurea are as described above for the pharmaceutical composition.
  • the oncolytic virus, the immune checkpoint inhibitor, and the hydroxyurea may be co-administered simultaneously, sequentially, or in reverse order. Specifically, the oncolytic virus, the immune checkpoint inhibitor, and the hydroxyurea may be administered simultaneously. In addition, the hydroxyurea may be administered first, followed by the immune checkpoint inhibitor, and then the oncolytic virus. The hydroxyurea may be administered first, followed by the oncolytic virus, and then the immune checkpoint inhibitor. The hydroxyurea may be administered first, followed by simultaneous administration of the oncolytic virus and the immune checkpoint inhibitor.
  • the oncolytic virus may be administered first, followed by the hydroxyurea, and then the immune checkpoint inhibitor.
  • the oncolytic virus may be administered first, followed by the immune checkpoint inhibitor, and then the hydroxyurea.
  • the oncolytic virus may be administered first, followed by simultaneous administration of the hydroxyurea and the immune checkpoint inhibitor.
  • the immune checkpoint inhibitor may be administered first, followed by the hydroxyurea, and then the oncolytic virus.
  • the immune checkpoint inhibitor may be administered first, followed by the oncolytic virus, and then the hydroxyurea.
  • the immune checkpoint inhibitor may be administered first, followed by simultaneous administration of the oncolytic virus and the hydroxyurea.
  • the hydroxyurea may be administered first, followed by the oncolytic virus, followed by the immune checkpoint inhibitor, and then the hydroxyurea again.
  • the hydroxyurea may be administered first, followed by the immune checkpoint inhibitor, followed by the oncolytic virus, and then the hydroxyurea again.
  • the hydroxyurea may be administered first, followed by simultaneous administration of the oncolytic virus and the immune checkpoint inhibitor, and then the hydroxyurea again.
  • the hydroxyurea may be administered first, followed by the oncolytic virus, followed by the hydroxyurea again, and then the immune checkpoint inhibitor.
  • the hydroxyurea may be administered first, followed by the immune checkpoint inhibitor, followed by the hydroxyurea again, and then the oncolytic virus.
  • the hydroxyurea may be administered first, followed by the oncolytic virus, followed by the hydroxyurea again, followed by the immune checkpoint inhibitor, and then the hydroxyurea again.
  • the hydroxyurea may be administered first, followed by the immune checkpoint inhibitor, followed by the hydroxyurea again, followed by the oncolytic virus, and then the hydroxyurea again.
  • the oncolytic virus may be administered first, followed by the hydroxyurea, followed by the immune checkpoint inhibitor, and then the hydroxyurea again.
  • the immune checkpoint inhibitor may be administered first, followed by the hydroxyurea, followed by the oncolytic virus, and then the hydroxyurea again.
  • a dosage of the oncolytic virus varies depending on the individual's condition and body weight, the severity of disease, the type of drug, the route and period of administration, and may be appropriately selected by a person skilled in the art.
  • the dosage may be such that a patient receives a vaccinia virus at 1 ⁇ 10 5 to 1 ⁇ 10 18 of virus particles, infectious virus units (TCID 50 ), or plaque forming units (pfu).
  • the dosage may be such that a patient receives an oncolytic virus at 1 ⁇ 10 5 , 2 ⁇ 10 5 , 5 ⁇ 10 5 , 1 ⁇ 10 6 , 2 ⁇ 10 6 , 5 ⁇ 10 6 , 1 ⁇ 10 7 , 2 ⁇ 10 7 , 5 ⁇ 10 7 , 1 ⁇ 10 8 , 2 ⁇ 10 8 , 5 ⁇ 10 8 , 1 ⁇ 10 9 , 2 ⁇ 10 9 , 5 ⁇ 10 9 , 1 ⁇ 10 10 , 5 ⁇ 10 10 , 1 ⁇ 10 11 , 5 ⁇ 10 11 , 1 ⁇ 10 12 , 1 ⁇ 10 13 , 1 ⁇ 10 14 , 1 ⁇ 10 15 , 1 ⁇ 10 16 , 1 ⁇ 10 17 , or higher of virus particles, infectious virus units, or plaque forming units, and various numerical values and ranges between the above-mentioned numerical values may also be included therein.
  • the oncolytic virus may be administered at a dose of 1 ⁇ 10 5 to 1 ⁇ 10 10 pfu. More preferably, the oncolytic virus may be administered at a dose of equal to or greater than 1 ⁇ 10 5 and lower than 1 ⁇ 10 9 pfu. In an embodiment of the present invention, the oncolytic virus was administered at 1 ⁇ 10 5 or ⁇ 10 7 pfu.
  • the hydroxyurea may be administered at a dose of 1 mg/kg/day to 100 mg/kg/day, or 10 mg/kg/day to 90 mg/kg/day. Specifically, the hydroxyurea may be administered at a dose of 10 mg/kg/day to 90 mg/kg/day, 15 mg/kg/day to 80 mg/kg/day, 20 mg/kg/day to 70 mg/kg /day, 25 mg/kg/day to 65 mg/kg/day, or 30 mg/kg/day to 60 mg/kg/day. In an embodiment of the present invention, the hydroxyurea was administered at 30 mg/kg/day or 60 mg/kg/day. Depending on the dosage, the hydroxyurea may be administered in divided doses several times a day. Specifically, the hydroxyurea may be administered 1 to 4 times a day or 1 to 2 times a day.
  • the immune checkpoint inhibitor may be administered at a dose of 0.1 mg/kg to 10 mg/kg, or 1 mg/kg to 5 mg/kg.
  • a dose of 0.1 mg/kg to 10 mg/kg, or 1 mg/kg to 5 mg/kg For example, for Opdivo Injection. that contains nivolumab as an active ingredient, 3 mg/kg may be administered via intravenous instillation over 60 minutes at 2-week intervals; and the usage and dose thereof as a combination therapy may be such that 1 mg/kg is administered via intravenous instillation over 30 minutes.
  • 200 mg may be administered via intravenous instillation over 30 minutes at 3-week intervals.
  • administration thereof is preferably performed in compliance with the usage and dose set by each manufacturer.
  • the oncolytic virus may be administered 1 to 10 times or 2 to 5 times, and may be administered to an individual at intervals of 7 to 30 days. Specifically, the oncolytic virus may be administered at intervals of 7 days, 14 days, 21 days, or 30 days.
  • the hydroxyurea may be administered before, during, or after administration of the oncolytic virus. Specifically, the hydroxyurea may be administered before or after administration of the oncolytic virus.
  • the hydroxyurea may be continuously administered once a day starting from 3 to 5 days before administration of the oncolytic virus, and may be continuously administered once a day for 9 to 28 days starting from within 24 hours of or after 24 hours of administration of the oncolytic virus.
  • the hydroxyurea may be continuously administered once a day starting from 1 to 3 days before administration of the oncolytic virus, and may be administered once a day for 13 days, 17 days, 18 days, or 28 days after administration of the oncolytic virus.
  • the immune checkpoint inhibitor may be administered before, during, or after administration of the oncolytic virus. Specifically, the immune checkpoint inhibitor may be administered after administration of the oncolytic virus.
  • the immune checkpoint inhibitor may be continuously administered at least once a week for 1 to 10 weeks after administration of the oncolytic virus. Specifically, the immune checkpoint inhibitor may be administered continuously at least twice a week for 1 to 8 weeks after administration of the oncolytic virus.
  • the cancer may be solid cancer or blood cancer.
  • the blood cancer may be any one selected from the group consisting of lymphoma, acute leukemia, and multiple myeloma.
  • the solid cancer may be any one selected from the group consisting of lung cancer, colorectal cancer, prostate cancer, thyroid cancer, breast cancer, brain cancer, head and neck cancer, esophageal cancer, skin cancer, thymic cancer, gastric cancer, colon cancer, liver cancer, ovarian cancer, uterine cancer, bladder cancer, rectal cancer, gallbladder cancer, biliary tract cancer, pancreatic cancer, and combinations thereof.
  • the hydroxyurea may be administered orally or parenterally. Specifically, the hydroxyurea may be administered parenterally, and such administration may be performed intraperitoneally or intravenously.
  • the immune checkpoint inhibitor may be administered intraperitoneally or intravenously.
  • the oncolytic virus may be administered parenterally, and such administration may be performed by any suitable method, such as intratumoral, intraperitoneal, subcutaneous, intradermal, intranodal, intravenous, or intraarterial administration. Among these, intratumoral, intraperitoneal, or intravenous administration may be preferred. Meanwhile, the dosages of the oncolytic virus, the immune checkpoint inhibitor, and the hydroxyurea may be determined according to the administration schedule, the dosage, and the patient's health condition.
  • the term "individual” refers to a person who has or is suffering from a disease in a state that may be alleviated, inhibited, or treated by administering the pharmaceutical composition of the present invention.
  • the term "administration” means introducing an effective amount of a substance into an individual by an appropriate method, and administration of the vaccinia virus and the hydroxyurea may be performed via a common route that allows the substances to reach a target tissue.
  • the oncolytic virus, the immune checkpoint inhibitor, and the hydroxyurea may be administered in combination with another drug or physiologically active substance whose therapeutic effect is known for the disease to be treated, or may be formulated in the form of a combination preparation with the other drug.
  • composition which includes an oncolytic virus, an immune checkpoint inhibitor, and hydroxyurea, for the prevention or treatment of cancer.
  • composition which includes an oncolytic virus, an immune checkpoint inhibitor, and hydroxyurea, for the manufacture of a medicament for treating cancer.
  • TK thymidine kinase
  • Wyeth strain NYC Department of Health
  • Western Reserve strain purchased from the American Type Culture Collection (ATCC).
  • ATCC American Type Culture Collection
  • a TK region in the wild-type vaccinia virus was subjected to substitution using a shuttle plasmid vector that contains firefly luciferase reporter (p7.5 promoter) gene or GFP gene.
  • HeLa cells (ATCC) were seeded in 6-well plates at 4 ⁇ 10 5 cells per well, and then culture was performed in EMEM medium containing 10% fetal bovine serum. Subsequently, treatment with the wild-type vaccinia virus was performed at an MOI of 0.05. 2 hours later, the medium was replaced with EMEM medium containing 2% fetal bovine serum, and then the cells were transfected with 4 ⁇ g of the shuttle plasmid vector, which was constructed in Preparation Example 1.1 and linearized, using Xfect TM polymer (Clonetech 631317, USA). Culture was performed for 4 hours.
  • the medium was replaced with EMEM medium containing 2% fetal bovine serum, and then culture was performed for 72 hours. Finally, the infected cells were collected, and then freezing and thawing were repeated 3 times. Subsequently, the cells were lysed by sonication, and a sucrose cushion method was used to obtain free oncolytic viruses, which were designated Wyeth VV tk- or WR VV tk- .
  • TK thymidine kinase
  • HSV1-TK herpes simplex virus thymidine kinase
  • a TK region in the Western Reserve strain wild-type vaccinia virus was subjected to substitution using (as a shuttle vector) pUC57amp+ plasmid (Genewiz, USA) into which synthesized mutated type 1 HSV-TK gene (pSE/L promoter) of SEQ ID NO: 1 and firefly luciferase reporter (p7.5 promoter) gene were recombined.
  • An oncolytic virus was obtained in the same manner as in Preparation Example 1.2 using the shuttle vector as constructed above, and this oncolytic virus was designated WOTS-418.
  • Balb/c mice female, 8-week-old purchased from ORIENT BIO (Busan, Korea) were subjected to a one-week acclimatization period, and then allografted with Renca cancer cell line (Korea Cell Line Bank) at 5 ⁇ 10 6 cells. The tumor volume was observed until it reached 200 mm 3 to 300 mm 3 , and then oncolytic virus (Wyeth VV tk- ) administration was started. The oncolytic virus has limited proliferation in an allograft model.
  • the group receiving intraperitoneal administration of saline was set as a negative control group
  • the group receiving the mouse PD-1 inhibitor the group receiving intratumoral administration of the oncolytic virus (Wyeth VV tk- , 1 ⁇ 10 7 pfu)
  • the group receiving co-administration of the oncolytic virus (Wyeth VV tk- , 1 ⁇ 10 7 pfu) and the PD-1 inhibitor were set as positive control groups.
  • the group receiving co-administration of the oncolytic virus (Wyeth VV tk- , 1 ⁇ 10 7 pfu), the PD-1 inhibitor, and hydroxyurea (30 mg/kg) was set as an experimental group.
  • the oncolytic virus was intratumorally administered once; the PD-1 inhibitor was intraperitoneally administered once every 2 days on days 14, 16, 18, and 20; and the hydroxyurea was intraperitoneally administered 6 times per week.
  • Tumor volumes were measured on days 0, 4, 10, 14, 17, and 21 after the drug administration to the mice of each group. As a result, it was identified that the tumor volume in the mice of the experimental group was significantly suppressed as compared with the tumor volume in the mice of the positive control groups ( FIG. 1 ).
  • Balb/c mice female, 8-week-old purchased from ORIENT BIO (Busan, Korea) were subjected to a one-week acclimatization period, and then allografted with Renca cancer cell line (Korea Cell Line Bank) at 5 ⁇ 10 6 cells. The tumor volume was observed until it reached 50 mm 3 to 150 mm 3 , and then oncolytic virus (Wyeth VV tk- ) administration was started. The oncolytic virus has limited proliferation in an allograft model.
  • the group receiving intraperitoneal administration of saline was set as a negative control group
  • the group receiving the CTLA-4 inhibitor the group receiving intratumoral administration of the oncolytic virus (Wyeth VV tk- , 1 ⁇ 10 7 pfu)
  • the group receiving co-administration of the oncolytic virus (Wyeth VV tk- , 1 ⁇ 10 7 pfu), the CTLA-4 inhibitor, and hydroxyurea (30 mg/kg) was set as an experimental group.
  • the oncolytic virus was intratumorally administered once; the CTLA-4 inhibitor was intraperitoneally administered once every 2 days on days 3, 5, 7, and 9; and the hydroxyurea was intraperitoneally administered 6 times per week.
  • Tumor volumes were measured on days 0, 4, 7, 10, 14, and 17 after the drug administration to the mice of each group. As a result, it was identified that the tumor volume in the mice of the experimental group was significantly suppressed as compared with the tumor volume in the mice of the positive control groups ( FIG. 2 ). From these results, it was identified that an excellent mouse renal cancer inhibition effect was exhibited in a case where hydroxyurea is also administered upon co-administration of an oncolytic virus and an immune checkpoint inhibitor (CTLA-4 inhibitor).
  • CTLA-4 inhibitor immune checkpoint inhibitor
  • Balb/c mice female, 8-week-old purchased from ORIENT BIO (Busan, Korea) were subjected to a one-week acclimatization period, and then allografted with Renca cancer cell line (Korea Cell Line Bank) at 5 ⁇ 10 6 cells. The tumor volume was observed until it reached 50 mm 3 to 100 mm 3 , and then oncolytic virus (Wyeth VV tk- ) administration was started. The oncolytic virus has limited proliferation in an allograft model.
  • the group receiving intraperitoneal administration of saline was set as a negative control group, the group receiving the PD-L1 inhibitor (300 ⁇ g/mouse), the group receiving intratumoral administration of the oncolytic virus (Wyeth VV tk- , 1 ⁇ 10 7 pfu), and the group receiving co-administration of the oncolytic virus (Wyeth VV tk- , 1 ⁇ 10 7 pfu) and the PD-L1 inhibitor were set as positive control groups.
  • the group receiving co-administration of the oncolytic virus (Wyeth VV tk- , 1 ⁇ 10 7 pfu), the PD-L1 inhibitor, and hydroxyurea (30 mg/kg) was set as an experimental group.
  • the oncolytic virus was intratumorally administered once; the PD-L1 inhibitor was intraperitoneally administered on days 0, 3, 7, 10, 14, 17, and 21; and the hydroxyurea was intraperitoneally administered 6 times per week.
  • Tumor volumes were measured on days 0, 3, 7, 10, 14, 17, and 21 after the drug administration to the mice of each group. As a result, it was identified that the tumor volume in the mice of the experimental group was significantly suppressed as compared with the tumor volume in the mice of the positive control groups ( FIG. 3 ). In particular, it was identified that in a case where comparison was made on the tumor volume before mouse sacrifice, the experimental group exhibited the tumor volume that is about 46% smaller than the group having received co-administration of the oncolytic virus and the PD-L1 inhibitor.
  • Balb/c mice female, 8-week-old purchased from ORIENT BIO (Busan, Korea) were subjected to a one-week acclimatization period, and then allografted with 4T1 cancer cell line (Korea Cell Line Bank) at 1 ⁇ 10 6 cells. The tumor volume was observed until it reached 50 mm 3 to 150 mm 3 , and then oncolytic virus (WR VV tk- ) administration was started.
  • the Western Reserve strain vaccinia virus-derived oncolytic virus (WR VV tk- ) has stronger proliferative capacity in an allograft model than Wyeth strain vaccinia virus-derived oncolytic virus.
  • the group receiving intraperitoneal administration of saline was set as a negative control group, the group receiving the CTLA-4 inhibitor (300 ⁇ g/mouse), the group receiving intratumoral administration of the oncolytic virus (WR VV tk- , 1 ⁇ 10 7 pfu), and the group receiving co-administration of the oncolytic virus (WR VV tk- , 1 ⁇ 10 7 pfu) and the CTLA-4 inhibitor were set as positive control groups.
  • the group receiving co-administration of the oncolytic virus (WR VV tk- , 1 ⁇ 10 7 pfu), the CTLA-4 inhibitor, and hydroxyurea (30 mg/kg) was set as an experimental group.
  • the oncolytic virus was intratumorally administered twice; the CTLA-4 inhibitor was intraperitoneally administered on days 3, 5, 7, and 9; and the hydroxyurea was intraperitoneally administered 6 times per week.
  • Tumor volumes were measured on days 0, 3, 7, 10, and 14 after the drug administration to the mice of each group. As a result, it was identified that the tumor volume in the mice of the experimental group was significantly suppressed as compared with the tumor volume in the mice of the positive control groups ( FIG. 4 ).
  • mice of the experimental group exhibited the best survival period and survival rate ( FIG. 5 ). From these results, it was identified that a significant effect was exhibited in a case where hydroxyurea is also administered upon co-administration of an oncolytic virus and a CTLA-4 inhibitor to mouse breast cancer cell-transplanted mice.
  • Balb/c mice female, 8-week-old purchased from ORIENT BIO (Busan, Korea) were subjected to a one-week acclimatization period, and then allografted with 4T1 cancer cell line (Korea Cell Line Bank) at 1 ⁇ 10 6 cells. The tumor volume was observed until it reached 50 mm 3 to 100 mm 3 , and then Western Reserve strain vaccinia virus-derived oncolytic virus (WOTS-418) administration was started. The Western Reserve strain has stronger proliferative capacity in an allograft model than the Wyeth strain.
  • the group receiving intraperitoneal administration of saline was set as a negative control group
  • the group receiving the PD-L1 inhibitor 300 ⁇ g/mouse
  • the group receiving intratumoral administration of the oncolytic virus WOTS-418, 1 ⁇ 10 7 pfu
  • the group receiving co-administration of the oncolytic virus WOTS-418, 1 ⁇ 10 7 pfu
  • the group receiving co-administration of the oncolytic virus (WOTS-418, 1 ⁇ 10 7 pfu), the PD-L1 inhibitor, and hydroxyurea (30 mg/kg) was set as an experimental group.
  • the oncolytic virus was intratumorally administered twice
  • the PD-L1 inhibitor was intraperitoneally administered on days 3, 5, 7, and 9
  • the hydroxyurea was intraperitoneally administered 6 times per week.
  • Tumor volumes were measured on days 0, 3, 7, 10, and 14 after the drug administration to the mice of each group in Experimental Example 5.1. As a result, it was identified that the tumor volume in the mice of the experimental group was significantly suppressed as compared with the tumor volume in the mice of the positive control groups ( FIG. 5 ). In particular, it was identified that in a case where comparison was made on the tumor volume before mouse sacrifice, the experimental group exhibited the tumor volume that is about 30% smaller than the group having received co-administration of the oncolytic virus and the PD-L1 inhibitor.
  • mice of each group had a higher survival rate than that in the mice of the negative and positive control groups.
  • mice purchased from ORIENT BIO (Busan, Korea) were subjected to a one-week acclimatization period, and then subcutaneously transplanted with a mouse colorectal cancer (CT-26) cell line (Korea Cell Line Bank) at 1 ⁇ 10 6 cells. After 7 days, the oncolytic virus (WR) and the PD-L1 inhibitor were intraperitoneally administered, and hydroxyurea was administered daily for 5 days from the next day.
  • CT-26 mouse colorectal cancer
  • WR oncolytic virus
  • PD-L1 inhibitor were intraperitoneally administered, and hydroxyurea was administered daily for 5 days from the next day.
  • the Western Reserve strain vaccinia virus has stronger proliferative capacity in an allograft model than Wyeth strain vaccinia virus.
  • the group receiving intraperitoneal administration of saline was set as a negative control group
  • the group receiving the PD-L1 inhibitor 200 ⁇ g/mouse alone
  • the group receiving co-administration of the oncolytic virus (WOTS-418) and hydroxyurea (30 mg/kg) were set as positive control groups.
  • the PD-L1 inhibitor, and hydroxyurea was set as an experimental group.
  • the oncolytic virus was intratumorally administered once
  • the PD-L1 inhibitor was intraperitoneally administered on days 1, 4, 8, and 11
  • the hydroxyurea was intraperitoneally administered 5 times per week.
  • mice of each group were analyzed. As a result, it was observed that the mice of the experimental group had the longest survival period as compared with the mice of the negative and positive control groups. From these results, it was identified that safety was improved in a case of co-administration of an oncolytic virus, an immune checkpoint inhibitor, and hydroxyurea.
  • Balb/c mice female, 8-week-old purchased from ORIENT BIO (Busan, Korea) were subjected to a one-week acclimatization period, and then allografted with Renca cancer cell line (Korea Cell Line Bank) at 5 ⁇ 10 6 cells. The tumor volume was observed until it reached 30 mm 3 to 50 mm 3 , and then Western Reserve strain vaccinia virus (WR) administration was started.
  • the Western Reserve strain vaccinia virus has stronger proliferative capacity in an allograft model than Wyeth strain vaccinia virus.
  • the group receiving intraperitoneal administration of saline was set as a negative control group
  • the group receiving co-administration of the Western Reserve strain vaccinia virus and the CTLA-4 inhibitor were set as positive control groups.
  • the group receiving administration of the Western Reserve strain vaccinia virus, the CTLA-4 inhibitor, and hydroxyurea was set as an experimental group.
  • the Western Reserve strain vaccinia virus was intratumorally administered once
  • the CTLA-4 inhibitor was intraperitoneally administered on days 2, 4. 6, and 8
  • the hydroxyurea was intraperitoneally administered 4 times per week.
  • Tumor volumes were measured on days 0, 3, and 7 after the drug administration to the mice of each group. As a result, it was identified that the tumor volume in the mice of the experimental group was significantly suppressed as compared with the tumor volume in the mice of the positive control groups ( FIG. 6 ).

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EP19943591.8A 2019-08-26 2019-08-26 Composition pharmaceutique pour le traitement du cancer comprenant un virus anticancéreux, un inhibiteur de point de contrôle immunitaire et une hydroxyurée en tant que principes actifs Pending EP4023232A4 (fr)

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